Drug-resistant bacterial pneumonia can induce dysregulated inflammation causing acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) leading to high morbidity and mortality in adult and pediatric populations. Current antimicrobial and/or anti-inflammatory agents typically fail to modulate the extent and intensity o the inflammatory cascade, resulting in an imbalance of immune functions, increasing the risk of secondary infection. We have identified human protein cystatin 9 (CST9) as a novel and effective immunotherapeutic approach to treat otherwise drug-resistant bacterial infections via modulation of pathogenic inflammation while promoting beneficial immune responses. Our proposal focuses on further evaluations of the human cysteine protease inhibitor CST9 and its development as a new therapeutic agent against pneumonia-related lung inflammation. Our findings showed the multifaceted immunoregulatory and antimicrobial functions of human recombinant (rCST9) whereby it modulated alveolar epithelial cell and macrophage inflammation, enhanced antibacterial immune responses to various Gram-negative pathogens, preserved lung integrity and directly interfered with bacterial pathogen replication. We hypothesize that rCST9 will modulate inflammation to combat lung damage and improve host survival in an experimental model of pneumonia caused by drug-resistant Delhi metallo-beta-lactamase-1 (NDM-1) producing Klebsiella pneumoniae (Kp). The objective and innovation of this proposal will be the optimization of rCST9 efficacy as a countermeasure against pneumonia (R21 phase) necessary for translation to drug development (R33 phase). We do not offer the opinion that rCST9 is a magic bullet for lung inflammatory diseases. But our data strongly support the diverse impacts of rCST9 on immune responses and pathogen virulence, making it ideally suited for more in-depth analyses as a promising therapeutic treatment (that may stand alone or be accompanied by additional therapeutic treatments) against pulmonary pathogens.